A novel pH‐controlled hydrogen sulfide donor protects gastric mucosa from aspirin‐induced injury

Abstract

Hydrogen sulphide (H2S) serves as a vital gastric mucosal defence under acid condition. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti‐inflammation. However, their inappropriate use causes gastric lesions and endogenous H2S deficiency. In this work, we reported the roles of a novel pH‐controlled H2S donor (JK‐1) in NSAID‐related gastric lesions. We found that JK‐1 could release H2S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL‐6 and TNF‐α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H2S generation in gastric mucosa, while up‐regulated cyclooxygenase (COX)‐2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre‐administration of JK‐1. However, JK‐1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES‐1) cells to HClO, imitating MPO‐driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre‐treatment with JK‐1. In conclusion, JK‐1 was proved to be an acid‐sensitive H2S donor and could attenuate ASP‐related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH‐controlled H2S donors in the future.

Recent Development of Hydrogen Sulfide Releasing/Stimulating Reagents and Their Potential Applications in Cancer and Glycometabolic Disorders

“…Recently, some controllable H 2 S donors have been developed. The representative examples are persulfide-based donors ( Zhao et al, 2013 ), N -mercapto-based donors ( Zhao et al, 2015 ), and JK type donors ( Kang et al, 2016 ; Yang et al, 2017a ), which are also shown in Figure 1 . These are considered “controllable” donors because their H 2 S release mechanisms are clearly exploited and the structural modifications could lead to H 2 S release profile changes (faster or slower).…”

Phosphonothioate-Based Hydrogen Sulfide Releasing Reagents: Chemistry and Biological Applications

“…PCL-JK1 was found to significantly enhance the wound repair and regeneration efficiency compared with PCL fiber alone, likely due to the ability of H 2 S to inhibit inflammation, reduce oxidative damage and increase angiogenesis. In another example, Yang et al (2017) demonstrated that the intragastrical (IG) pre-administration of JK-1 protects gastric mucosa from aspirin (ASP)-induced gastric mucosal injury in vivo . Preconditioning with JK-1 alleviated ASP-induced inflammation response which was further validated by decreased levels of pro-inflammatory factors IL-6 and TNF-α.…”

Exogenous Hydrogen Sulfide Within the Nucleus Ambiguus Inhibits Gastrointestinal Motility in Rats

“…Hydrogen sulfide (H 2 S) is an essential neuromodulator in mammals (Zheng et al, 2018), which regulates numerous pathophysiological functions in the digestive, respiratory, circulatory and nervous systems (Kimura et al, 2012;Drapala et al, 2017;Yang et al, 2017;Yu et al, 2017;Zhou et al, 2018). Endogenous H 2 S levels have been detected in the brains of rats and humans (Wang, 2012;Yang and He, 2019).…”